The protease tissue plasminogen activator (tPA) has been implicated in neuronal death in the central nervous system (CNS). We have now found that tPA also affects neurons after damage in the peripheral nervous system (PNS). In the mouse sciatic nerve, tPA is up-regulated by Schwann cells after crush injury, suggesting a role in either protecting the tissue or contributing to the damage. To investigate this question, we examined mice that lack either tPA or plasminogen. Both genotypes have exacerbated damage after crush, indicating that the tPA/plasminogen system is a beneficial response of the tissue to injury. We have also found that fibrin is extensively deposited in the injured nerve. Removal of fibrin genetically or pharmacologically from mice protects their sciatic nerve from the increased injury observed in the absence of tPA or plasminogen. These results indicate that the role of the tPAlplasminogen system is to clear fibrin from the injured nerve. We have also found that fibrin deposition inhibits the regenerative phase after injury. This application proposes to extend this work by: 1), determining themechanism by which fibrin deposition inhibits sciatic nerve regeneration; 2) analyzing the role of the tPA/plasminogen system in mouse and rat models of CNS degeneration in great detail; and 3) evaluating new methods for fibrin removal as therapeutic strategies to reduce nerve damage and promote regeneration.